Local Recurrence and Distant Metastases after Breast Conservation Treatment in Women with Triple Negative Breast Cancer Subtype

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1 Local Recurrence and Distant Metastases after Breast Conservation Treatment in Women with Triple Negative Breast Cancer Subtype Amr Ghannam 1, Omnia Abd el-fattah 1 and Ayman El-Nemr 2 1 Clinical Oncology and 2 Surgical Oncology Departments, Faculty of Medicine, Tanta University omniaabdelfattah@yahoo.com Abstract: Introduction: Recently, gene expression studies using DNA microarrays have identified five common subtypes of breast cancer. The triple negative (TN) phenotype, which includes tumors that do not express ER, PR, or HER2 serves as a proxy for the basal-like subtype. At the present time, there is little clinical data evaluating whether a particular breast cancer subtype is associated with increased rates of local and/or distant recurrence after BCT.Objective: to evaluate the outcome after breast conservation therapy for triple-negative early-stage invasive breast carcinoma. Materials and methods: Between 2000 and 2010, 421 patients with early stage breast cancer patients who treated with BCT were classified as TN (58) if they were negative for all three receptors (ER, PR, and HER2/neu) or as non TN (363) if they were positive for any of the three markers. These patients were evaluated for isolated local and distant recurrence. Results: The local relapse rates among the TN group were nearly equal to those of the non TN. (5.2% vs. 3.9% P= 0.63) five-years overall and disease free survival of the TN group were significantly poorer than the other group( 62% vs 85 % p=0.002 ) and (39 % vs 75% p= 0.00 ). The isolated local relapse free survival was 90.3% vs 95.7% between the 2 groups. (P= 0.365) while the isolated distant metastases free survival was 52% vs 84%. (P= 0.00). Conclusions: Although women with TN tumors had a higher rate of local failure and a lower rate of freedom from distant metastases compared with women without TN tumors, the absolute difference was relatively small and is not statistically significant and therefore does not preclude BCT for women with TN early-stage invasive breast carcinoma. [Amr Ghannam, Omnia Abd el-fattah and Ayman El-Nemr. Local Recurrence and Distant Metastases after Breast Conservation Treatment in Women with Triple Negative Breast Cancer Subtype. Life Sci J 2012;9(3): ]. (ISSN: ).. 26 Keywords: Breast Cancer, Hormone Receptor Negative, HER-2/neu Local recurrence. 1. Introduction Breast cancer encompasses a heterogeneous population of tumors characterized by a variety of clinical, pathological, and molecular features [1-3]. Molecular markers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) have been used to classify patients into different subtypes. Recently, gene expression studies using DNA microarrays have identified five common subtypes of breast cancer: luminal A (ER or PR positive and HER2 negative), luminal B (ER or PR positive and HER2 positive), HER2 overexpressing (ER and PR negative and HER2 positive), basal-like (ER, PR, and HER2 negative, CK 5/6 positive) and normal breast-like tumor [2,4-6]. HER2 overexpressing and basal-like subtypes are significantly more likely to be grade 3 and are associated with worse recurrence rates and decreased overall survival [3,5-7]. The triple negative (TN) phenotype, which includes tumors that do not express ER, PR, or HER2 on immunohistochemistry (IHC), serves as a proxy for the basal-like subtype with a positive predictive value of approximately 80-97% [8,9]. Although this approach is not complete, several groups have adopted a TN definition for basal-like cancer out of convenience. Several randomized trials have demonstrated molecular markers were available. The data on ER, PR, and HER2/neu were obtained through standard clinical testing, using immunohistochemistry for ER and PR and the HER2/neu. For ER and PR, receptor positivity was based on more than 10% of cells testing positive. HER2/neu scores of 0 and 1 were considered negative, and Positive HER2 was determined using either IHC 3+ staining or amplification on fluorescence in situ hybridization (FISH) in patients with IHC 2+. Patients were classified as triple negative if they were negative for all three receptors or as non triple negative if they were positive for any of the three markers. Exclusion criteria for this study included male breast cancer, T3 disease, mastectomy, previous or concurrent malignancy (breast or other site)or patients treated without radiotherapy. All patients were treated with breast-conserving surgery followed by radiation therapy. The surgical treatment included complete gross excision of the primary tumor. Re-excision of the primary tumor was done if possible if positive margin was proved. Pathologic axillary lymph node staging was performed for all patients. Earlier in the study period, pathologic axillary lymph node staging was generally performed 175

2 using a lower axillary lymph node that survival rates following breast-conserving treatment (BCT) were equivalent to those observed with radical mastectomy [10-12]. Given these results, BCT has become an accepted treatment for early stage breast cancer [13]. At the present time, there is little clinical data evaluating whether a particular breast cancer subtype is associated with increased rates of local and/or distant recurrence after BCT [14-17]. The outcome after breast conservation treatment with radiation has not been well described for triplenegative early-stage invasive breast carcinoma. Therefore, the current study was performed to evaluate the outcome after breast conservation treatment with radiation for this subtype of breast carcinoma. 2. Materials and Methods Between the year 2000 and 2010, 759 patients with American Joint Committee on Cancer stages I-II (18) disease were treated with breast-conserving surgery followed by radiation therapy to the intact breast, with or without systemic therapy, at the Clinical Radiation Oncology Department, Tanta University hospital. Only those patients in whom ER, PR, and HER2/neu status were available were included in the current analysis. This limited the sample to a total of 421 patients in whom all three was defined as clinical evidence of distant disease based on clinical and/or radiographic findings. All events were calculated from the time of surgery to the time of the event. For the calculation of overall survival (OS), a death due to any cause was scored as a failure. For the calculation of freedom from distant metastases, a failure was scored at the time of first evidence of distant metastatic disease. The Kaplan-Meier method was used to calculate OS, freedom from distant metastases, local failure, and distant failure (19). The time period was defined as the time of surgery of breast carcinoma. The logrank test was used for statistical comparisons between groups (20) Multivariate analysis was performed using the Cox proportional hazards model (21). Chi - square test was used to compare the characteristics of patients between the 2 groups. All statistical methods was done using SPSS statistical package version Results In our series, 421 patients were classified according to ER, PR, and HER2 into either TN (58) or non TN (363) patients. TN patients represent about 14 % of the whole study group. Patients, tumor, and treatment characteristics of each group are detailed in table(1). there is a highly significant difference between both groups regarding age with about 45% of triple negative patients less than 40 years compared to 33% of non triple negative patients. The median age for patients with TN breast carcinoma was 41 years while the median age for patients without a triple negative breast carcinoma was 47 years. There was no significant difference between patients by T-size, LN status, grade, extensive intraductal component, tumor necrosis, lymphovascular invasion or resection margin. All triple negative patients received chemotherapy compared to 83% of patients in the other group. The most common regimens used were either CMF or FAC or FAC and taxanes. All eligible patients underwent BCS and post operative whole breast irradiation. For the radiation treatment to the whole breast, the median dose was 46 Gy (mean, Gy; range, Gy). The median total dose was 61 Gy (mean, Gy; range, Gy). Among non triple negative groups, 80,7% of patients received hormone therapy. Few patients with HER 2 overexpression received adjuvant trastuzumab therapy. During the follow up period, there were 3 (5.2%) and 14 (3.9%) patients in TN and non TN groups respectively who experienced isolated local in breast relapse as the first site of recurrence. the difference was non significant(p= 0.63 ). Isolated distant relapse was observed in 19(32.8 %) and 47(12.9 %) patients in TN and non TN groups respectively(p= 0.00 ). The 5-years OS and DFS rates of all patients were 82% and 71% respect. Groups respectively (P= 0.00) By multivariate Cox proportional hazard models, lymph node status, intraductal component, and use of adjuvant systemic treatment were significant prognostic factors affecting OS. Age, tumor size, lymph node status and use of systemic treatment significantly affected DFS (Table2) 4. Discussion There has been much attention focused on TNBCs since the first identification of basal-like cancers using microarray expression profiling studies in 2005 (22). There is a significant overlap between TNBCs, which are defined by immunohistochemistry, and basaloid like tumors, which are identified from gene expression profiling, such that those two entities are frequently considered synonymous from a clinical perspective.(23-24) 176

3 Table (1): Patients characteristics. AGE Tumor size L.N. GRADE EIC Necrosis Triple negative N=58 Receptors Non -triple negative N=363 Total Chi-square N % N % N % X 2 P-value <40 y >40 y T T N N N G G G Positive Negative unknown yes no unknown yes LVI RM Systemic treatment Isolated local recurrence Isolated distant recurrence no unknown negative positive close Chemotherapy alone Hormonal alone both present absent present absent Table (2): Cox proportional hazards multivariate model for overall (OS) and disease-free survival (DFS) Variable OS DFS HR 95% CI p-value HR 95% CI p-value AGE TSIZE LN grade EIC necrosis LVI Tumor subtype Systemic treatment

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5 Figure 1. Cumulative incidence of local recurrence as the first event TNBCs have a poor prognosis and do not respond to therapy directed at known breast cancer growth factor targets, including hormonal therapy and trastuzumab. TNBCs are fast-growing tumors, usually have a high histologic grade, and tend to metastasize earlier compared with breast cancers that express hormone receptors (16,25). The predominant sites of metastases for TNBCs differ from the luminal subtype. They are more frequently node negative and spread, in70%of patients, to the lung and brain, whereas luminal cancers tend to metastasize, in 70% of patients, to the bone and liver. (16,22.) TNBC tumors seem to be more sensitive to chemotherapy, and although there is a sharp decrease in survival early after diagnosis, survival plateaus after 8 to 10 years (16). In the current study, we evaluated 421 patients with conservatively treated breast cancer in whom all three markers were available to validate the prognostic utility of this classification scheme and to determine whether triple negative breast cancers have a more aggressive locoregional and distant relapse rate. Among all patients included, the triple negative cohort still had a poorer prognosis than the non triple negative cohort, but the two cohorts had a similar local relapse-free survival ( 90.3 vs 95.7 in TN and non TN groups respectively, P= 0.365). In fact, the local relapse rates among the triple negative cohort were nearly equal to those of the non triple negative cohort (5.2% and 3.9% of patients in TN and non TN groups P= 0.63 ). This is of particular importance given the fact that triple negative patients are significantly younger, and younger women have been shown to have a higher rate of local relapse compared with older women(26-31), therefore, those patients should not be 179 considered poor candidates for breast-conserving therapy. The fact that these women with triple negative tumors had similar local relapse rates indicates that these tumors are not radiation resistant. This is consistent with the fact that these basal-like tumors are theoretically responsive to DNA-damaging agents and should, therefore, be relatively radiation sensitive. Larger patient cohorts with a longer follow-up will be required to further validate these data. Only limited data are available for local control after breast conservation treatment with radiation relative to biologic subtype. Haffty et al reported that there was no significant difference in local failure at 5 years for the triplenegative subgroup versus the non triple-negative subgroup (17% vs. 17%, respectively; P =.82) (14). Nguyen et al., reported the outcome for patients grouped according to ER status, PgR status, and HER2 status as a surrogate for biologic subtype of disease (15). The 5-year rate of local recurrence was 7.1% for the basal-like (triple-negative) subgroup, 8.4% for the HER2 subgroup, 1.5% for the luminal B subgroup, and 0.8% for the luminal A subgroup. In comparison with the luminal A subgroup, there was an increased rate of local failure for the basal-like (triple-negative) subgroup (P =.0099) and the HER2 subgroup (P =.012). In a study evaluating HER2 as a single factor, Harris et al., reported no difference in local failure at 5 years for the HER2-positive group compared with the HER2-negativegroup (0% vs. 2%, respectively; P =.15) (32). Parikh et al., reported an increased rate of local recurrence for premenopausal patients with CK19- negative tumors compared with CK19-positive tumors (relative risk, 3.54; P <.01) (33). For 3038 patients treated with either breast conservation treatment or mastectomy, Cheang et al., used a panel of tumor markers to define biologic subtype of disease (34). The 10-year rate of local relapse was 7% for the luminal A subgroup, 11% for the luminal B subgroup, 15% for the luminal/her2- positive subgroup, 15% for the basal-like subgroup, and 18% for the HER2-positive subgroup. For 1601 patients treated with either mastectomy or breast conservation, Dent et al., reported no significant difference in local failure for the triple-negative group compared with the non triple-negative group (HR, 0.8; P =.38) (16). There are emerging data for using genomic factors to predict the risk of local recurrence after breast conservation treatment. Using a 21-gene recurrence score assay, Mamounas et al evaluated the risk of local-regional recurrence for patients treated in the National Surgical Adjuvant Breast and Bowel Project B-14 and B-20 trials for patients with nodenegative, ER-positive breast cancer (35). After breast

6 conservation treatment with radiation for 390 patients, there was a strong interaction of localregional failure with age. For patients aged < 50 years, the 10-year rate of local-regional failure was 12.5% for tumors with a low-risk recurrence score, 27.7% for tumors with an intermediate-risk recurrence score, and 26.5% for tumors with a highrisk recurrence score (P =.057). However, the 10- year rates of local-regional recurrence were relatively low for patients aged 50 years, regardless of the results of the recurrence score assay (3.6% vs. 3.7% vs. 4.8%, respectively; P =.663). Nuyten et al., reported that the wound response signature obtained by gene expression profiling was able to segregate the patients after breast conservation treatment into a high risk versus a low risk of local recurrence at 10 years (29% vs. 5%, respectively; P =.0008) (36). The wound signature profile remained a significant predictor for local recurrence on multivariate analysis (P =.01) Freedman et al., (17) defined three groups: ER or PR (+), HER2, and TN. Patients in the TN and HER2 groups were more likely to have T2 and grade 3 diseases. The median age of the TN and HER2 groups was both 54 years, which was also older than that of the present study. They also reported that there was no overall difference in total locoregional recurrence rates between the three groups (p=0.13). Additionally, a higher rate of distant metastases in the HER2 group was observed (11.9%, p=0.009) which translated into a lower recurrence-free survival rate (84%, p=0.005). It is also notable that, despite the use of adjuvant systemic chemotherapy, triple negative patients seemed to have a poor prognosis, with a distant metastasis-free survival rate of only 52% at 5 years. The interpretation of these findings remains debatable given the relatively small number of patients and the retrospective nature of this study, and further studies evaluating the impact of adjuvant systemic therapy in triple negative patients is warranted. By definition of their lack of receptors for ER, PR, and HER2/ neu, patients with triple negative tumors are not candidates for adjuvant hormonal therapy or trastuzumab (37). Basal-like tumors have been shown to overexpress HER1 (epidermal growth factor), and patients with these tumors may be candidates for prospective studies evaluating targeted antibodies against epidermal growth factor that are already in clinical use (5,38). Clearly, additional prospective and retrospective studies are warranted to further refine prognosis and optimize treatment in patients with triple negative breast cancers. We have demonstrated here, using the simple commonly available markers of ER, PR, and HER2/neu, that patients with triple negative breast cancers have a relatively poor prognosis, with a poorer distant metastasis-free, disease-free, and Overall survival. The current study has several potential limitations. Firstly, because HER2 testing has evolved over time, there was not uniform testing for all of the breast carcinomas in the current study. Second, the relatively small number of patients in the triple-negative subset limited the power to detect small, but potentially statistically significant, differences. Whether alternative forms of chemotherapy for these breast cancer patients, with or without biologic modifiers, will prove superior can only be addressed by well-designed prospective studies. Third, the groups were differentiated based on tumor markers, not gene profiling. Nonetheless, segregating patients into prognostic groups on the basis of tumor markers is clinically relevant, particularly in view of targeted therapies currently available. Another potential weakness of the study is unavoidable selection biases in a retrospective series such as this. For the current study, only patients who had available ER, PR, and HER2/neu data were included. Finally, the patients were treated largely before the routine use of trastuzumab and lapatinib. Thus, the results in the current study, particularly for the HER2-positive patients, could be substantially different for patients treated using newer targeted therapies. 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